Esters a-amino

In the present preparation, ethyl acetoacetate is treated with sufficient nitrous acid to convert half into the a-nitroso (or a-oximino) ester, which is reduced by zinc and acetic acid to the a-amino ester (I). The latter then condenses with... 

Aziridine-2-carboxylates 12 (Scheme 3.4) have also been prepared from 3-hy-droxy-a-amino esters 9 by treatment with sulfuryl chloride in place of tosyl or mesyl chloride. Treatment of 9 with thionyl chloride in the presence of triethylamine, followed by oxidation of 10 with sodium periodate and a catalytic amount of... 

Cydization of P-hydroxy-a-amino esters under Mitsunobu reaction conditions is an alternative approach to aziridine-2-carboxylic esters [6b, 13-16], In this case the P-hydroxy group is activated by a phosphorus reagent. Treatment of Boc-a-Me-D-Ser-OMe 13 (Scheme 3.5) with triphenylphosphine and diethyl azodicarboxylate (DEAD), for example, gave a-methyl aziridinecarboxylic acid methyl ester 14 in 85% yield [15]. In addition to PPh3/DEAD [13b, 15], several other reagent combi-... 

Ring-opening of aziridine-2-carboxylates with alcohols has been reported to give (3-alkoxy-a-amino esters [16, 102]. Treatment of as-aziridine 127 (Scheme 3.45) with alcohol in the presence of a catalytic amount of boron trifluoride etherate afforded P-alkoxy-ot-amino esters 128 in 57-100% yields [16,102a], The reaction is both regio- and stereoselective, affording 128 as the only product. 

E)-alkene dipeptide isostere 48, 51, 63 alkenylepoxide 42 alkoxy carbonyl protecting group 32 P-alkoxy-a-amino esters... 

In general, metalated 2-azaallyl anions derived from imines of a-amino esters serve both as Michael donors and as 1,3-dipolar reagents the course of the reaction, as well as the stereochemical outcome depends upon the base and the reaction conditions82,83. 

Dipolar [3 + 2] cycloadditions are one of the most important reactions for the formation of five-membered rings [68]. The 1,3-dipolar cycloaddition reaction is frequently utihzed to obtain highly substituted pyrroHdines starting from imines and alkenes. Imines 98, obtained from a-amino esters and nitroalkenes 99, are mixed together in an open vessel microwave reactor to undergo 1,3-dipolar cycloaddition to produce highly substituted nitroprolines esters 101 (Scheme 35) [69]. Imines derived from a-aminoesters are thermally isomerized by microwave irradiation to azomethine yhdes 100,... 

A library of 800 substituted prolines of type 112 was described using a similar synthetic approach. The [3 + 2] cycloaddition occurred via a multicomponent reaction of a-amino esters, aldehydes, and maleimides (Scheme 38). 

A very elegant approach has been developed by Kanerva et al. DKR of N-hetrocyclic a-amino esters is achieved using CAL-A [54]. Racemization occurs when acetaldehyde is released in situ from the acyl donor. In this case aldehyde-catalyzed racemization of the product cannot occur (Figure 4.28). This is one of the few examples reported for DKR of secondary amines (For a recent example see the above text and Ref. [38]). 

The condensation of nitrilimines with a-amino esters gives l,4-dihydro-l,2,4-triazin-6-ones6 <94MI01 96CA(124)55907>. 

Perez-Fuertes et al.6 8 have suggested the possibility of using the three-component chiral derivatizing approach for prediction of the absolute configuration of amines. Comparison of aH NMR spectra has shown significantly more deshielded signals of (S,S)-imino-boronate esters, derivative of a-amino esters than (S,R) diastereomers. 

Imidazopyrimidopyrimidines such as 324 can be prepared simply by treatment of the pyrimidines 323 with isocyanates and isothiocyanates derived from a-amino esters (Equation 112) <1998HCA646>. 

Alkylation of a-amino esters with 9-bromo-9-phenylf uorene serves as the principal step in the preparation of N-(9-phenylfluoren-9-yl)-a-amino carbonyl compounds which are useful chiral educts for asymmetric synthesis. A discussion of the synthetic utility of N-9-phenylfluoren-9-yl derivatives of amino adds and amino acid esters appears in the procedure following. 

Scheme 6.186) [347]. The condensation of O-allylic and O-propargylic salicylalde-hydes with a-amino esters was carried out either in the absence of a solvent or - if both components were solids - in a minimal volume of xylene. All reactions performed under microwave conditions rapidly proceeded to completion within a few minutes and typically provided higher yields compared to the corresponding thermal protocols. In the case of intramolecular alkene cycloadditions, mixtures of hexa-hydrochromeno[4,3-b]pyrrole diastereoisomers were obtained, whereas transformations involving alkyne tethers provided chromeno[4,3-b]pyrroles directly after in situ oxidation with elemental sulfur (Scheme 6.186). Independent work by Pospisil and Potacek involved very similar transformations under strictly solvent-free conditions [348]. 

In 2001, Sarko and coworkers disclosed the synthesis of an 800-membered solution-phase library of substituted prolines based on multicomponent chemistry (Scheme 6.187) [349]. The process involved microwave irradiation of an a-amino ester with 1.1 equivalents of an aldehyde in 1,2-dichloroethane or N,N-dimethyl-formamide at 180 °C for 2 min. After cooling, 0.8 equivalents of a maleimide dipo-larophile was added to the solution of the imine, and the mixture was subjected to microwave irradiation at 180 °C for a further 5 min. This produced the desired products in good yields and purities, as determined by HPLC, after scavenging excess aldehyde with polymer-supported sulfonylhydrazide resin. Analysis of each compound by LC-MS verified its purity and identity, thus indicating that a high quality library had been produced. 

Microwave-induced 1,3-dipolar cycloadditions involving azomethine ylides have been widely reported in the literature. Bazureau showed that imidates derived from a-amino esters 120, as potential azomethine ylides, undergo 1,3-dipolar cyclo-additions with imino-alcohols 121 in the absence of solvent under microwave irradiation. This reaction leads to polyfunctionalized 4-yliden-2-imidazolin-5-ones 122 (Scheme 9.36) [87]. 

Treatment of a-amino esters with sulfonamide in the presence of DBLJ at 160°C also affords 2-unsubstituted-l,2,5-thiadiazolidin-3-one 1,1-dioxides 199 in moderate yield <2005SL834>. 

As is also illustrated in Scheme 6.23, the optically enriched amino nitriles can be converted to the corresponding a-amino esters through a four-step sequence (74—> 75). Unlike the aforementioned imine alkylations with alkylzinc reagents, methylation of the phenolic OH is required, since the corresponding o-methoxy aniline is less reactive and affords significantly lower enantioselectivities similar observations are made when aniline is used. 

The low percentage of obtaining products belonging to the a-kainic acid series (at best 50%) was attributed to unfavorable transition states with repulsion between one of the aminomalonate ester groups and the isoprenyl chain. These difficulties were circumvented by using a simple a-amino ester (131) in lieu of the aminomalonate group this has led to a simple synthesis of a-kainic acid (Scheme 33) (178). 

Micelle-forming copper complexes were found to effectively discriminate between enantiomers in the hydrolysis of a-amino esters (257). Hydrolysis of (.V)-phenylalanine p-nitrophenyl ester is 14-fold faster than its enantiomer, Eq. 223. Leucine affords 10-fold faster hydrolysis. The authors note that the micellar nature of these systems is extremely important for both rate of hydrolysis and selectivity (258). For example, the /V-mcthyl-dcrivcd ligand 419b leads to inhibition of the hydrolysis process, relative to catalysis by Cu(II) ion alone. 

Similarly, treatment of a-tosylamino-substituted allene 83 provided the expected a-amino ester 232 in good yield [74], The analogous reaction could also be performed with methoxyallene-aziridine adduct 46, which furnished enantiomerically pure /3-amino acid 233 [46], Although the ozonolysis approach seems to constitute a versatile and flexible method for the construction of a-amino and a-hydroxy esters, only a few examples have been reported so far. 

A-Benzylimines have also been reported to react with acrylonitriles under solidrliquid conditions in which the initial anionic intermediate undeigoes an intramolecular nucleophilic ring closure to produce a diastereoisomeric mixture of the pyrrolidine (Scheme 6.23) [30-32], Similar cyclized products have been reported for the reaction of benzylidene-protected a-amino esters and vinyl ketones [33, 34],... 

Conversely, activated methylene compounds undergo an addition reaction across the C=N bond of imines. For example, benzylic ketones react with benzylidene anilines to from P-aminoketones [35], whereas the analogous reaction of diphenyl-methylene-protected a-amino esters, and nitriles, produces a disastereomeric mixture of the A-protected a,p-diamino esters, and nitriles [36, 37]. 

Only limited precedent exists for the stereoselective enolization and subsequent condensation of a-heteroatom-substituted esters 48a and 48b (eq. [29]). Ireland has examined the enolization process for a-amino ester derivatives where the Claisen rearrangement (chair-preferred transition states) was employed to ascertain enolate geometry (Scheme 10) (43). These results imply that 48a [X = N(CH2Ph)2 ] exhibits only modest selectivity for ( )-enoIate formation under the... 

The enolization (LDA, THF) and subsequent condensation of a-amino ester 53a under kinetic conditions affords low levels of kinetic aldol diastereoselection. From the preceding discussion it is probable that the major enolate derived from 53a possesses the E)-geometry. The observation that moderate levels of erythro diastereoselection are observed with benzaldehyde (Table 16) are consistent... 

Cram and co-workers have experimented extensively with chiral recognition in crown ethers derived from various 3-binaphthols (73). In nonpolar solvents, these chiral ethers complex salts of PEA and various chiral a-amino esters (with fast exchange), inducing nonequivalence in their NMR spectra. The senses of proton nonequivalence induced in these solutes have been used to support proposed structures of the diastereomeric solvates (74). 

Intramolecular cyclization DKP formation through intramolecular cyclization of the Nj—C2 bond is an efficient route to ring closure and the construction of these head-to-tail dipeptides involves the coupling of an N-protected a-amino acid to an a-amino ester, followed by N-deprotection and cyclization. " ... 

The fourth method also involves a tandem bond-forming strategy of N1-C2 and N4—C5, in which simultaneous formation of both amide bonds of a 2,5-DKP occurs in a one-pot reaction from an a-amino ester derivative. ... 

FeCl2 has been used to catalyse nitrene transfer from l-butyloxycarbonyl azide to sulfoxides (to form sulfoximides), sulfides (to give sulfimides), and a ketene acetal (to form an a-amino ester). ... 

Potassium enolates derived from the chiral Schiff bases obtained by reaction of racemic a-amino esters with 2-hydroxypinan-3-one undergo diastereoselective protonation, as evidenced by release of optically active a-amino esters on subsequent cleavage of the imine (Scheme 5). ... 

In 2007, AntiUa and coworkers disclosed the first asymmetric organocatalytic reduction of acyclic a-imino esters (Scheme 23) [39], Chiral VAPOL phosphate (5)-16 (5 mol%) served as a catalyst for the transfer hydrogenation of the latter (62) employing commercially available dihydropyridine 44a to give both aromatic and aliphatic a-amino esters 63 in very high yields (85-98%) and enantioselectivities (94-99% ee). 

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